Imprinted Genes and Human Disease: An Evolutionary Perspective

Abstract

Imprinted genes have been associated with a wide range of diseases. Many of these diseases have symptoms that can be understood in the context of the evolutionary forces that favored imprinted expression at these loci. Modulation of perinatal growth and resource acquisition has played a central role in the evolution of imprinting and many of the diseases associated with imprinted genes involve some sort of growth or feeding disorder. In the first part of this chapter, we discuss the relationship between the evolution of imprinting and the clinical manifestations of imprinting-associated diseases. In the second half, we consider the variety of processes that can disrupt imprinted gene expression and function. We ask specifically if there is reason to believe that imprinted genes are particularly susceptible to deregulation—and whether a disruption of an imprinted gene is more likely to have deleterious consequences than a disruption of an unimprinted gene.

There is more to a gene than its DNA sequence. C. H. Waddington used the term “epigenetic” to describe biological differences between tissues that result from the process of development1,2. Waddington needed a new term to describe this variation which was neither the result, of genotypic differences between the cells nor well described as phenotypic variation. We now understand that heritable modifications of the DNA—such as cytosine methylation—and aspects of chromatin structure—including histone modifications—are the mechanisms underlying what Waddington called the “epigenotype”. Epigenetic modifications are established in particular cell lines during development and are responsible for the patterns of gene expression seen in different tissue types.

In contemporary usage, the term epigenetic refers to heritable changes in gene expression that are not coded in the DNA sequence itself3. In recent years, much attention has been paid to a particular type of epigenetic variation: genomic imprinting. In the case of imprinting, the maternally and paternally inherited genes within a single cell have epigenetic differences that result in divergent patterns of gene expression4. In the simplest scenario, only one of the two alleles at an imprinted locus is expressed. In other cases, an imprinted locus can include a variety of maternally expressed, paternally expressed and biallelically expressed transcripts5, 6, 7, 8, 9, 10. Some of these transcripts produce different proteins through alternate splicing, while others produce noncoding RNA transcripts11, 12, 13, 14, 15. Genomic imprinting can also interact with the “epigenotype” in Waddington’s sense: many genes are imprinted in a tissue-specific manner, with monoallelic, expression in some cell types and biallelic expression in others16, 17, 18, 19, 20.

Other chapters in this volume cover our current understanding of the mechanisms of imprinting, the phenotypic effects of imprinted genes in mammals and what we know about imprinting in plants. In this chapter we discuss the link between imprinted genes and human disease. First, we consider the phenotypes associated with imprinted genes and ask whether the disorders associated with these genes share a common motif. Second, we consider the nature and frequency of mutations of imprinted genes. We ask whether we should expect that imprinted genes are particularly fragile. That is, are they more likely to undergo mutation and/or are mutations of imprinted genes particularly likely to result in human disease? In general we consider how the field of evolutionary medicine—the use of evolution to understand why our body’s design allows for the existence of disease at all21—might contribute to our comprehension of disorders linked to genomic imprinting.